Caplyta
lumateperone
Species
RatMouseDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog (mouse up to 3 months)
“The toxicological profile of lumateperone was studied in mice, rats, and dogs following oral administration for up to 3, 6, and 9 months, respectively.”
Why that species
No species matched human metabolism (monkey, hamster, guinea pig, minipig tested); rat and dog used
“The Applicant was unable to identify an alternative nonclinical species with a similar metabolic profile to humans and, therefore, the rat and dog were used.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In the rat 6-month chronic toxicology study, adverse effects occurred at doses of lumateperone that are ~ 5 times the MRHD of 42 mg on a mg/m2 basis.”
Species: general tox
Mouse (3 months), rat (6 months) and dog (9 months); oral
“The toxicological profile of lumateperone was studied in mice, rats, and dogs following oral administration for up to 3, 6, and 9 months, respectively.”
Species: DART
Rat and rabbit (embryo-fetal development)
“In animal reproduction studies, no malformations were observed with oral administration of lumateperone to pregnant rats and rabbits during organogenesis at doses up to 2.4 and 9.7 times, respectively, the maximum recommended human dose (MRHD) of 42 mg/day on a mg/m 2 basis.”
Species: carcinogenicity
Rat and mouse (oral, up to 21 months)
“Its carcinogenic potential was studied following oral administration for up to 21 months in rats and mice, providing additional information on its toxicology.”
Surrogate used in
No surrogate used; no species matched human metabolism, so rat and dog were used
“The Applicant was unable to identify an alternative nonclinical species with a similar metabolic profile to humans and, therefore, the rat and dog were used.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month dog)
“The toxicological profile of lumateperone was studied in mice, rats, and dogs following oral administration for up to 3, 6, and 9 months, respectively.”
Pivotal GLP studies
6-month rat and 9-month dog oral studies; 3-month mouse
“The toxicological profile of lumateperone was studied in mice, rats, and dogs following oral administration for up to 3, 6, and 9 months, respectively.”
Route in tox
Oral (capsules in dog)
“Route of administration: Oral Capsules”
Skipped studiesopen answer page →
Genotoxicity
Ames and mouse lymphoma positive only with metabolic activation; negative rat micronucleus and Comet
“Lumateperone was positive for mutagenic potential in the Ames test in the presence of metabolic activation in the TA1537 tester strain and the mouse lymphoma test. Lumateperone was negative for clastogenic activity in the in vivo micronucleus assay in rats and was not genotoxic in the in vivo Comet assay in rats”
Carcinogenicity
Lifetime rat and mouse studies: no carcinogenic potential
“Lifetime carcinogenicity studies were conducted in rats and mice, and results showed no carcinogenic potential in either species.”
Reproductive & developmental
Impaired male and female rat fertility and estrus irregularities at ~MRHD
“Oral administration of lumateperone to male and female rats adversely affected male and female fertility and caused estrus cycle irregularities at doses approximately equal to the MRHD of 42 mg lumateperone on a mg/m2 basis.”
Safety pharmacology
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Genotox: Ames
Positive in TA1537 with metabolic activation; negative without
“Lumateperone was positive for mutagenic potential in the Ames test in the presence of metabolic activation in the TA1537 tester strain and the mouse lymphoma test.”
Genotox: in vitro mammalian
Mouse lymphoma assay: positive with metabolic activation, negative without
“Lumateperone was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) or the mouse lymphoma test in the absence of metabolic activation. Lumateperone was positive for mutagenic potential in the Ames test in the presence of metabolic activation in the TA1537 tester strain and the mouse lymphoma test.”
Genotox: in vivo
Rat micronucleus and rat Comet assays: negative (~16x MRHD, mg/m2)
“Lumateperone was negative for clastogenic activity in the in vivo micronucleus assay in rats and was not genotoxic in the in vivo Comet assay in rats at doses ~16 times the MRHD of 42 mg on a mg/m2 basis.”
Carcinogenicity model
Lifetime rat and mouse studies; no carcinogenic potential
“Lifetime carcinogenicity studies were conducted in rats and mice, and results showed no carcinogenic potential in either species.”
Carcinogenicity timing
Carcinogenicity study reports submitted April 2018, before the final NDA portion (September 2019)
“The nonclinical study reports for the carcinogenicity studies were submitted on April 19, 2018 and April 26, 2018. The Applicant submitted the final portion of the NDA on September 27, 2019.”
hERG / QT
No hERG assay result reported; (Q)SAR models flagged structural alerts for hERG inhibition
“(Q)SAR models for hERG channel inhibition and drug-induced phospholipidosis identified structural alerts for all but the glucuronide metabolite, suggesting that metabolites containing the aniline moiety do not exhibit distinctively different effects at these endpoints.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Caplyta don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Dog CNS adverse effects at 4x MRHD; NOAEL 2x MRHD (mg/m2 basis) (FDA multi-discipline review, p. 41)
NOAEL / key findings
Dog CNS adverse effects at 4x MRHD; NOAEL 2x MRHD (mg/m2 basis)
“Adverse effects in the central nervous system of dogs occurred at doses of lumateperone that are 4 times the MRHD of 42 mg on a mg/m2 basis. The dose of lumateperone that corresponds to the NOAEL was 2 times the MRHD of 42 mg on a mg/m2 basis.”
Risksopen answer page →
Immune & cytokine safety
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Biodistribution & persistence
Prolonged uveal tract/retina retention (up to 840 h), suggesting melanin binding
“Notably the uveal tract/retina contained 64% and 42% of peak concentrations of radioactivity 336 hr and 840 hr post-dose, respectively, indicating lumateperone-related material may bind to melanin.”
Modality-specific risk
Systemic intracytoplasmic pigment accumulation with little to no exposure margin
“Oral administration of lumateperone caused systemic intracytoplasmic accumulation of pigmented material in dogs, rats, and mice, with little to no exposure margin relative to the 42-mg MRHD on both a mg/m2 and AUC plasma exposure basis.”
Anti-drug antibodies: animals
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Anti-drug antibodies: patients
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Label warnings
Boxed warning: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS; and SUICIDAL THOUGHTS AND BEHAVIORS
- Increased Mortality in Elderly Patients with Dementia-Related Psychosis
- Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients
- Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis
- Neuroleptic Malignant Syndrome
- Tardive Dyskinesia
- Metabolic Changes
- Leukopenia, Neutropenia, and Agranulocytosis
- Orthostatic Hypotension and Syncope
- Falls
- Seizures
- Potential for Cognitive and Motor Impairment
- Body Temperature Dysregulation
- Dysphagia
PsychiatricCardiovascularSecondary malignancySkin reactionsMetabolic & endocrineCytopeniasNeurotoxicityGastrointestinal
US prescribing information, Boxed Warning and Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Caplyta don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Dog CNS adverse effects at 4x MRHD; NOAEL 2x MRHD (mg/m2 basis) (FDA multi-discipline review, p. 41)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month oral beagle dog study; recovery not stated
“Study title/ number: 9-Month Oral Toxicology and Toxicokinetic Study of ITI-007 in Beagle Dogs”
Pivotal GLP studies
6-month rat and 9-month dog oral studies; 3-month mouse
“The toxicological profile of lumateperone was studied in mice, rats, and dogs following oral administration for up to 3, 6, and 9 months, respectively.”
DART package
Species: DART
Rat and rabbit (embryo-fetal development)
“In animal reproduction studies, no malformations were observed with oral administration of lumateperone to pregnant rats and rabbits during organogenesis at doses up to 2.4 and 9.7 times, respectively, the maximum recommended human dose (MRHD) of 42 mg/day on a mg/m 2 basis.”
Reproductive & developmental
Impaired male and female rat fertility and estrus irregularities at ~MRHD
“Oral administration of lumateperone to male and female rats adversely affected male and female fertility and caused estrus cycle irregularities at doses approximately equal to the MRHD of 42 mg lumateperone on a mg/m2 basis.”
PPND / ePPND: when
Rat pre- and postnatal study (organogenesis through lactation) completed before the marketing application
“When pregnant rats were administered lumateperone during the period of organogenesis through lactation, the number of perinatal deaths of pups was increased at 4.9 times the MRHD, with no adverse effects on pups at 2.4 times the MRHD”
Carcinogenicity
Species: carcinogenicity
Rat and mouse (oral, up to 21 months)
“Its carcinogenic potential was studied following oral administration for up to 21 months in rats and mice, providing additional information on its toxicology.”
Carcinogenicity model
Lifetime rat and mouse studies; no carcinogenic potential
“Lifetime carcinogenicity studies were conducted in rats and mice, and results showed no carcinogenic potential in either species.”
Carcinogenicity timing
Carcinogenicity study reports submitted April 2018, before the final NDA portion (September 2019)
“The nonclinical study reports for the carcinogenicity studies were submitted on April 19, 2018 and April 26, 2018. The Applicant submitted the final portion of the NDA on September 27, 2019.”
Safety marginopen answer page →
Safety margin at NOAEL
Dog NOAEL 2x the MRHD of 42 mg (mg/m2 basis)
“The dose of lumateperone that corresponds to the NOAEL was 2 times the MRHD of 42 mg on a mg/m2 basis.”
NOAEL / key findings
Dog CNS adverse effects at 4x MRHD; NOAEL 2x MRHD (mg/m2 basis)
“Adverse effects in the central nervous system of dogs occurred at doses of lumateperone that are 4 times the MRHD of 42 mg on a mg/m2 basis. The dose of lumateperone that corresponds to the NOAEL was 2 times the MRHD of 42 mg on a mg/m2 basis.”
Efficacy evidenceopen answer page →
Efficacy evidence
Rodent models of antipsychotic activity: head twitch, conditioned avoidance, amphetamine-induced hyperlocomotion
“Lumateperone displayed in vivo functional activity in several rodent models of antipsychotic activity including 5-HT2 receptor agonist-induced head twitch in rats and mice (study Nos. ITI DPI001 & ITI-007 INT IC200131, Inhibition of DOI-Induced Head Twitch), conditioned avoidance response (study No. ITI DPI002), and inhibition of amphetamine-induced hyperlocomotion in rats”
Why that model
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Reviewer's view of the efficacy data
Data support postsynaptic D2 antagonism but are insufficient to establish presynaptic D2 antagonist or partial agonist activity
“In conclusion, the in vitro and in vivo data indicate that lumateperone is a postsynaptic D2 receptor antagonist; however, they do not provide enough evidence to establish antagonist or partial agonist activity at presynaptic D2 receptors.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesAccepted with a conditionBeyond the letter
Rat and dog used although neither matches human metabolism; dog and rat form aniline metabolites not quantifiable in humans
Why: No alternative species (monkey, hamster, guinea pig, minipig) had a human-like metabolic profile · Other reason
“The Applicant was unable to identify an alternative nonclinical species with a similar metabolic profile to humans and, therefore, the rat and dog were used.”
“Therefore, these animal findings need to be described in the label as the nonclinical studies could not definitively establish that they are of no clinical relevance.”
Safety marginAccepted with a conditionBeyond the letter
Pigment accumulation in dogs, rats and mice with little to no exposure margin to the 42 mg MRHD
“Oral administration of lumateperone caused systemic intracytoplasmic accumulation of pigmented material in dogs, rats, and mice, with little to no exposure margin relative to the 42- mg MRHD on both a mg/m2 and AUC plasma exposure basis.”
“In conclusion, from a nonclinical perspective, the application is considered approvable pending the description of the relevant findings in animals in section 13.2 of the label.”
RecoveryQuestioned
Recovery from CNS, heart and retinal pigment accumulation assessed over only 1 to 2 months
“Apparently irreversible pigment accumulation was observed in the brain and spinal cord in all three species, and in cardiomyocytes and the retina of rats, although, recovery was assessed over a relatively short period of time (1 to 2 months).”
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